API and IP Newsletter
Contents
FDA approvals in September 2022
On 29 September 2022 FDA approved RELYVRIO. A new treatment for amyotrophic lateral sclerosis, or ALS.
It is developed by Amylyx Pharmaceuticals. This oral medication can be taken as a standalone therapy or with other treatments, according to the company, and it has been shown to slow disease progression.
But there’s still some uncertainty about the drug’s efficacy. Amylyx’s submission for approval is based on data from a small Phase 2 trial, and the FDA’s own advisory committee initially voted this spring that the data didn’t show that the drug was effective, before changing its opinion this month. A larger Phase 3 study is still underway.
As per the press release, the 28-day prescription of RELYVRIO will be priced at $12,504, about $158,000 per year before insurance. Here.
RELYVRIO contains two active ingredients: sodium phenylbutyrate and taurursodiol.
The chemical designation for phenylbutyrate is 4-phenyl butyric acid sodium salt. Its molecular weight is 186.2. The sodium phenylbutyrate chemical structure is:
Sodium phenylbutyrate is a white or yellow powder which decomposes at about 220 °C. It is freely soluble in water and methanol; sparingly soluble in ethanol; and practically insoluble in methylene chloride, acetone, and diethyl ether.
Taurursodiol, also known as tauroursdeoxycholic acid, is an ambiphilic bile acid and is the taurine conjugate of ursodiol, also known as ursodeoxycholic acid. The chemical name of taurursodiol is 2-[(3α, 7β-dihydroxy-24-oxo-5β-cholan-24-yl) amino] ethane sulfonic acid, dihydrate. The molecular weight is 535.74 (dihydrate). The taurursodiol chemical structure is:
Taurursodiol is a white microcrystalline powder, practically odourless, with a bitter taste. It is freely soluble in ethyl alcohol, very slightly soluble in acetone and dioxane, sparingly soluble in water, and practically insoluble in ether and ethyl acetate.
RELYVRIO is a white to yellow powder for oral suspension that consists of fine to large granules. RELYVRIO is supplied in a packet containing 3 g sodium phenylbutyrate (equivalent to 2630 mg phenylbutyrate) and 1 g taurursodiol.
Both active ingredients are very old compounds.
There are several suppliers of both active compounds are reported. Anthem Bioscience, Alkem and few others are importing tauroursdeoxycholic acid.
General information
Advaxis enters merger deal with biotech firm Ayala
Ayala Pharmaceuticals has signed a definitive merger agreement with biotechnology company Advaxis, which discovers, develops and markets immunotherapies.
Advaxis’ immunotherapies are based on a technology that leverages engineered Listeria monocytogenes. The business combination would result in a merged company that will mainly focus on developing and marketing Ayala’s AL102 and Advaxis’ ADXS-504.
A lead candidate of Ayala, AL102 is intended to treat desmoid tumours, while ADXS-504 is being developed for prostate cancer.
News here.
Drugs Should Be Priced Based On One Factor – Value
For several years, the price of drugs has drawn extraordinary attention. Based on the current discourse, one would think that the nation’s healthcare costs were dominated by medicines. Drugs account for less than 15% of all medical spending. Yet, the clamor raised about drug prices has been such that Congress, as part of the Inflation Reduction Act, for the first time gave Medicare the power to dictate the price of drugs. One would have thought that this step would lessen the issue of drug pricing.
Unfortunately, a recent paper in the Journal of the American Medical Association entitled “Association of Research and Development Investments With Treatment Costs for New Drugs Approved From 2009 to 2018” has proven otherwise. The authors provide data to show that the price of drugs has little to do with the research and development expenses generated in bringing new medicines to market.
News here.
Intellectual Property
T 2269/19 (Pharmaceutical compositions comprising Prasugrel / KRKA) of 14.7.2022
EP 2398468 was issued to Krka based on 17 claims.
Claim 1 of the patent read as follows:
"A process of forming a compressed mixture comprising
a.) an effective amount of prasugrel base or its pharmaceutically acceptable salt,
b.) pharmaceutically acceptable additives suitable for the preparation of solid oral dosage forms, characterized in that lactose is not used,
by solvent free technological methods comprising the steps of
i.) optionally grinding the active agent and pharmaceutical additives, mixing them, or mixing them first and grinding them together,
ii.) subjecting a homogenous mixture of the active agent and additives to compression, the average particle size of prasugrel or its pharmaceutically acceptable salt being in the range of 0.2 µm to 150 µm."
Claim 7 read as follows:
"Pharmaceutical composition comprising or consisting of a compressed mixture, said compressed mixture being obtainable according to the process of claim 1."
Without going into too many details, one can note patent was upheld at the first instance and matter was under appeal. We will briefly discuss obviousness and how the Board of Appeals (hereafter the Board) opined on Obviousness issues.
Key prior art cited were following among others
D1: WO 2006/135605 A2
D6: Pharmaceutical Dosage Forms: Tablets, Vol. 1, 2**(nd) ed., p. 1-24
Obviousness
According to patentee, the skilled person would refrain from reducing the particle size of prasugrel to the recited range of 0.2-150 µm, for two reasons: firstly, D6 taught that lower particle sizes or grinding may lead to drawbacks in terms of e.g. stability, aggregation, flowability or dissolution rate (see page 6, penultimate paragraph, and table 2); and secondly, prasugrel HCl was known to be soluble and have rapid bioavailability, such that the skilled person would have no motivation to improve its bioavailability.
Contrary to the patentee’s opinion, the Board said, the fact that D1 ( WO 2006/135605 A2) addresses the problem of improving stability and shelf life of prasugrel compositions, the skilled person, faced with the problem of providing an alternative to D1, would consider modifying any well-known parameter of the pharmaceutical composition, such as the particle size of the active ingredient.
The choice of the average particle size specified in claim 1 in the absence of any associated effect, arbitrary and does not involve an inventive step. The broad range 0.2-150 µm does not depart from the values which the skilled person would routinely select.
On the contrary, D6, which reflects the common general knowledge in the field, generally indicates that particles above approximately 100 µm should be ground, that grinding is not necessary when the particles are around 30 µm or less of diameter, and that the grinding should reduce coarse material to preferably 10-40 µm
The Board remarked, the fact that this passage of D6 refers to "new drugs" does not mean that the skilled person would disregard its application to the known drug prasugrel, because the expression "new drug" is of no technical relevance to the suitability of a given particle size for the formulation of a drug.
Furthermore, the Board pointed out the fact that D6 generally recommends the range of 10-40 µm while mentioning the possible influence of particle size / grinding on e.g. stability, solubility and bioavailability, means that this range is recommended in view of these factors. Hence there is no indication in D6 that the recommended range is unsuitable for formulation of a drug.
Patentee further referred to the data in table 2 of D6, in which an active agent particle size of 387 µm provides the highest stability. However, these data only pertain to a different active ingredient, namely sulfacetamide, and, in as far as they depart from the general recommendation in D6, would be regarded as an exception rather than the rule.
Consequently, the skilled person would know, from common general knowledge as reflected in D6, that particle sizes in the range of 10-40 µm are in general suitable for the preparation of solid pharmaceutical compositions and would therefore consider that using this particle size in the case of prasugrel would solve the technical problem of providing an alternative to D1.
Accordingly, the Board opined prosecuted claims do not meet the requirements of inventive step. Patent was revoked.
